Epithelial cancers, or carcinomas, account for greater than 90% of all human cancers. In particular, cancers of the stratified epithelia, such as the skin and the tissues of the head and neck, are common, and can display poor prognosis in advanced stages. Perturbations in cell-cell adhesion play an important part in late stages of cancer, where they can facilitate invasion and metastasis. Although loss of adherens junction function is established to be important for tumor progression and metastasis, the role of the related adhesion junction, the desmosome, in cancer is poorly understood. Specifically, while studies have suggested that desmosome components are downregulated during tumor progression in humans, genetic studies to examine the role of desmosome inactivation in cancer using knockout mice have not been performed. We recently found that the Perp tetraspan membrane protein, which we originally identified as a target of the p53 tumor suppressor, is also an effector of the p63 stratified epithelial development program, where it plays an essential role in desmosome function and epithelial integrity. As is common with desmosome component knockout mice, Perp null mice display lethality, and thus the Perp conditional knockout mice we generated will provide a unique means to assess the contribution of desmosome loss in cancer, through ablation of Perp in a spatially and temporally regulated manner. Thus, to understand the role of desmosomes in cancer, we propose to use the Perp-deficient mice we have generated to examine the consequence of Perp loss in multiple tumor models, both in vitro and in vivo. In addition, although Perp is essential for desmosomal adhesion, the means by which it promotes desmosome function is unknown. Therefore, to define Perp's mechanism of action, we will generate a panel of Perp mutants to map important functional domains involved in adhesion and suppressing tumorigenesis. In conjunction with experiments we will perform to identify Perp-interacting desmosomal proteins and to characterize their role in tumorigenesis. These studies will help reveal whether Perp function in suppressing cancer relates to its ability to promote adhesion or another function. Together, these approaches will help elucidate how Perp, and desmosomes, contribute to epithelial integrity and cancer, and will provide insight into p63 function in cancer. An understanding of the factors affecting cancer progression ultimately will be important for better diagnosis, prognosis and therapy.